PROJECT SUMMARY Global access to combination antiretroviral therapy (cART) has turned HIV infection from a death sentence to a manageable, chronic illness in which co-infections and comorbidities become increasingly important. In particular, persons living with HIV-1 infection (PLWH) are prone to suffering from accelerated/premature aging (A/PA) that exacerbates non-AIDS morbidity and mortality, often regardless of social and economic status. Although the potential culprits can range from unhealthy lifestyle and adverse effects of antiretrovirals to chronic inflammation/immune activation (residual HIV replication or microbial translocation) and deterioration of immunologic health, including immune senescence and immune exhaustion, our own research has uncovered clear evidence that A/PA is a highly heterogeneous outcome because many PLWH have been subjected to a genetic selection before 1996 (the dawn of cART era). In other words, heritable genetic factors that differentially mediate metabolism, infection, immunity, and immunopathology (e.g., autoimmune disorders) can obscure the interpretation of A/PA. Accordingly, we aim to study immunogenetic profiles and immunologic features that may readily distinguish PLWH subgroups from age- and gender-matched control (HIV-) subjects from the general population. Specifically, Aim 1 will examine the distribution of biologically and functionally relevant genetic variants in 526 (342 HIV+ and 184 HIV-) youth and 2,028 (652 HIV+ and 1,376 HIV-) adults, with a focus on single nucleotide polymorphisms (SNPs) and human leukocyte antigen (HLA) variants that are known or predicted to be causal factors for 21 autoimmune conditions, including psoriasis (a common inflammatory disease) that is expected to rise in PLWH populations. Genotyping data from youth and adult populations (2,554 total subjects) will test a central hypothesis that PLWH who managed to do well without cART are genetically distinct, especially in terms of immunogenetic profiles that protect them from HIV pathogenesis, while predisposing them to autoimmune disorders. Aim 2 will further examine trajectories of immunologic health in PLWH youth and adults stratified by favorable and unfavorable genetic profiles, primarily through analyses of inflammatory cytokines, chemokines, and cellular markers of lymphocyte and monocyte activation or exhaustion. Overall, these multidisciplinary studies will open new avenues for translational research on autoimmunity and HIV-related A/PA in the highly heterogeneous PLWH populations.